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Update on Neuromuscular Relaxants

Update on Neuromuscular Relaxants. Charles E. Smith, MD Professor of Anesthesia Case Western Reserve University Director, Cardiothoracic Anesthesia MetroHealth Medical Center Cleveland, Ohio. Objectives. Mechanism of action Monitoring Pharmacology non-depolarizers depolarizers

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Update on Neuromuscular Relaxants

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  1. Update on Neuromuscular Relaxants Charles E. Smith, MD Professor of Anesthesia Case Western Reserve University Director, Cardiothoracic Anesthesia MetroHealth Medical Center Cleveland, Ohio

  2. Objectives • Mechanism of action • Monitoring • Pharmacology • non-depolarizers • depolarizers • Reversal

  3. Historical • 1942: dTC, long-acting, histamine • 1952: sux • 1954: 6 fold  in mortality with dTC • 1967: panc, long acting, CV stimulation • 1986: interm acting relaxants: • vec: no CV effects • atrac: Hoffman elimination, histamine • 1990 to present: newer agents to fill specific niche • roc, cis, miv, pip, dox; rap: withdrawn from market

  4. Classical Mechanism of Action • Non-depolarizers: • competitive block • prevent binding of Ach to receptor • Depolarizers- • mimic action of Ach • excitation followed by block Drachman, NEJM

  5. Postjunctional Nicotinic AchR Taylor: Anesthesiology 1985;63:1-3

  6. Standaert FG: 1984

  7. Margin of Safety • Wide margin of safety of neuromuscular transmission • 70% receptor occupancy before twitch depression • Receptor alterations • burns, MG, quadra- +hemiplegia

  8. TOF Monitoring • TOF: • 4 supramaximal stimuli at 2 Hz, every 0.5 sec • observe ratio of 4rth twitch to first • Loss of all 4 twitches: • profound block • Return of 1-2 twitches: • sufficient for most surgeries • Return of all 4 twitches: • easily “reversible” Viby-Mogensen, 1984

  9. Onset + Recovery of NM Block A-Nondepolarizing. B- Sux. Viby-Mogensen: BJA 1982;54:209

  10. Terminology • Efficacy: ability of drug to produce a desired effect • Potency: quantity of drug to produce maximum effect • Biologic variability: individual variation in response to identical dose of drug • DRC: • measure efficacy and potency • compare drugs, disease states

  11. Concept of “Effective Dose” • ED90: dose that produces 90% block (+ SD) in average patient at standard muscle group • Usually adductor pollicis- ulnar nerve • Derived from dose-response studies • Intubating dose: 2- 3 x ED90 • Repeat doses: < ED90

  12. DRC- show differences in potency, slope, efficacy + individual responses. Stoelting + Miller, 2000

  13. Altered Dose-Response • Some muscle groups more resistant- DRC shifted to right: • diaphragm, larynx, eye, abdominal • Some muscle groups more sensitive- DRC shifted to left: • pharyngeal muscles, upper airway • muscles of the thumb Donati F: Semin Anesth 2002;21:120; Donati F: Anesthesiology 1986;65:1

  14. Rocuronium: Larynx v. Thumb Muscles of the larynx, diaph, + eye are more resistant to non-depolarizers v. thumb Meistelman: CJA 1992;39:665-9

  15. Elimination • Most NMBA: 2 compartment models: redistribution, then elimination • a) NM junction  non-effector site tissue • b) elimination from plasma • Exceptions: sux, miv, atrac, cistrac

  16. Two Compartment Model Stanski 1982. Drug Disposition in Anesthesia

  17. Stanski, 1982. Drug Disposition in Anesthesia

  18. Volume of Distribution • Calculated number, [conc] = dose / Vd • Inject known amount of drug • Measure plasma concentration • Does not refer to anatomic volumes • reflects volume of compartments that drug is distributed in • influenced by: protein binding, degree of ionization + water solubility

  19. Altered Vd •  Vd:  [conc] for any given dose • neonates • burns • hepatic failure • cardiopulmonary bypass •  Vd:  [conc] for any given dose • elderly • shock • CHF

  20. Vecuronium • ED90: 0.04 mg/kg • intubating dose: 0.1-0.2 mg/kg • onset: 2-4 min, clinical duration: 30-60 min • Maintenance dose: 0.01-0.02 mg/kg, duration: 15-30 min • Metabolized by liver, 75-80% • Excreted by kidney, 20-25% • ½ life : 60 minutes • Prolonged duration in elderly + liver disease • No CV effects, no histamine release, no vagolysis • May precipitate after thiopental

  21. Concerning rocuronium, which are true? • Onset delayed compared with vec (equipotent doses) • Onset faster at the diaphragm compared with muscles of the thumb • Duration is longer than that of equipotent doses of vecuronium • Duration is shorter in elderly patients compared with young adults

  22. Rocuronium • ED90: 0.3 mg/kg • intubating dose: 0.6-1.0 mg/kg • onset: 1-1.5 minutes, clinical duration: 30-60 min • Maintenance dose: 0.1-0.15 mg/kg, duration: 15-30 min • Metabolized by liver, 75-80% • Excreted by kidney, 20-25% • ½ life : ~ 60 minutes • Mild CV effects- vagolysis, no histamine release, • Prolonged duration in elderly + liver disease • Only non-depolarizer approved for RSI

  23. Cisatracurium • ED90: 0.05 mg/kg • intubating dose: 0.2 mg/kg • onset: 2-4 minutes, clinical duration: 60 min • Hofmann elimination: not dependent on liver or kidney for elimination • Predictable spontaneous recovery regardless of dose • ½ life : ~ 60 minutes • No histamine release • CV stability • Agent of choice for infusion in ICU Prielipp et al: Anesth Analg 1995;81:3-12

  24. Succinylcholine • ED90: 0.3 mg/kg • intubating dose: 1.0-1.5 mg/kg • onset: 30-45 sec, clinical duration: 5-10 min • can be given IM or sublingual • dose to relieve laryngospasm: 0.3 mg/kg • Maintenance dose: no longer used • Metabolized by pseudocholinesterase • prolonged duration if abnormal pc (dibucaine # 20) • Prolonged effect if given after neostigmine •  dose requirement for non-depolarizers after sux

  25. Concerning sux, which are true? • Bradycardia + nodal rhythms unlikely after “2nd dose” sux • Hyperkalemia + cardiac arrest unlikely 1 week after major burns, or in children with Duchenne’s muscular dystrophy • Contraindicated in patients with head injury • May cause malignant hyperthermia or masseter spasm • Duration unaffected by prior administration of neostigmine

  26. Succinylcholine + Arrhythmias • Bradycardia, nodal rhythms, asystole • Especially after 2nd dose: give atropine, 0.6 mg, IV prior Stoelting R, Miller RD: 2000

  27. Head Injury + Sux Kovarik, Mayberg, Lam: Anesth Analg 1994;78:469-73

  28. Succinylcholine Adverse Effects • Malignant hyperthermia, masseter spasm •  IOP, myalgias,  intragastric pressure •  ICP: doubtful significance • Hyperkalemia + cardiac arrest in “at risk patients” • Receptor alterations: denervation, burns • Myopathy rhabdomyoslysis Bevan DR: Semin Anesth 1995;14:63-70

  29. Sux + Hyperkalemia • Burns, Hemiplegia, Paraplegia, Quadraplegia: •  extrajunctional receptors after burn or denervation • Danger of hyperkalemia with sux: 48 hrs post injury until …? • Muscular Dystrophies: • Others: • severe infections, closed head injury, crush, rhabdo, wound botulism, necrotizing pancreatitis • Tx of Hyperkalemia: Bevan DR, Bevan JC, Donati F: 1988

  30. Residual NM Block • 1979: 42% incidence with long acting drugs [Viby-Mogensen] • 1988:  incidence with vec + atrac [Bevan, Smith, Donati- Mtl] • 1992:  ventilatory response to hypoxia, TOF 0.6-0.7 • 1997:  pharyngeal muscle coordination with TOF 0.6-0.8 • 1997: panc is risk factor for postop pulmonary complications [v. vec + atrac; RCT n= 693 patients] • 2003: 45% incidence with interm acting drugs w/o reversal, TOF 0.9 [Debaene, Plaud, Donati- France] Berg: Acta Anaesthesiol Scand 1997;41:1096. Eriksson: Anesthesiology 1993+1997

  31. Elimination Half-Life, t 1/2  Time for conc to decrease by 1/2

  32. Double Burst • TOF fade: difficult to detect clinically until < 0.2 • Use double burst: • 2 short bursts of tetanic stimulation separated by 750 ms • Easier to detect fade + residual block, 0.2-0.7 Viby-Mogensen, 2000

  33. Reversal of NM Block • Clinical practice: • if no evidence block + 4 half-lives: omit reversal • if still evidence block: give reversal • if unsure: give reversal • Rule of thumb: • if 2 twitches of TOF visible, block is usually reversible • if no twitches visible, best to wait (check battery) • Neostigmine 2.5 mg/Glycopyrolate 0.5 mg • do not omit anti-cholinergic!

  34. Org 25969: A safer way to reverse NMB? • Gijsenbergh et al, Anesthesiology 2005;103;695-703. Belgium • Modified cyclodextrin • Encapsulates roc • Promotes dissociation of roc from AchR • Phase 1 study, n=29 • No recurarization

  35. + Roc Org 25969 = Gijsenbergh et al. Anesthesiology 2005;103:695

  36. Adductor pollicis acceleromyography- TOF watch

  37. How Much Relaxation? • Muscle relaxants do not make the hole bigger. • They do not relax bone • They do not decompress bowel • They do not give a surgeon judgement • They do not relax fat Bevan DR: Can J Anaesth 1995;42:93. Quote from the internet 10/94

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